Formulations for treating or preventing mucositis

ABSTRACT

Mucositis is treated and/or prevented by administrating to a patient a formulation comprising a tetracycline that is poorly absorbed from the gastro-intestinal tract. The tetracycline may be in the form of a pharmaceutically acceptable salt or a base. The formulations may optionally also contain an antifungal agent to prevent fungal overgrowth due to reduction in the normal oral flora by the tetracycline. Such compositions have the advantage of treating the entire gastro-intestinal tract since the active ingredient is not removed from the tract via absorption. Further, such compositions minimize systemic exposure and accompanying side effects.

This application claims priority to U.S. Ser. No. 60/153,892 filed Sep.14, 1999.

FIELD OF THE INVENTION

The present application relates generally to formulations containing atetracycline that are useful for treating or preventing mucositis.

BACKGROUND OF THE INVENTION

Mucositis is a dose-limiting side effect of cancer therapy and bonemarrow transplantation and is not adequately managed by currenttreatment (Sonis, 1993a, “Oral Complications,” in: Cancer Medicine, pp.2381-2388, Holand et al.; Eds., Lea and Febiger, Philadelphia; Sonis,1993b, “Oral Complications in Cancer Therapy,” In: Principles andPractice of Oncology, pp. 2385-2394, De Vitta et al., Eds., J. B.Lippincott, Philadelphia). Oral mucositis is found in almost 100% ofpatients receiving radiotherapy for head and neck tumors, in about 40%of patients receiving chemotherapy, and in about 90% of children withleukemia (Sonis, 1993b, supra). Complications related to oral mucositis,though varying in the different patient populations, generally includepain, poor oral intake with consequent dehydration and weight loss, andsystemic infection with organisms originating in the oral cavity leadingto septicemia (Sonis, 1993b; U.S. Pat. No. 6,025,326 to Steinberg etal.). In addition to the oral cavity, mucositis may also affect otherparts of the gastro-intestinal tract.

A variety of approaches to the treatment of oral mucositis andassociated oral infections have been tested with limited success. Forexample, the use of an allopurinol mouthwash, an oral sucralfate slurry,and pentoxifyline were reported in preliminary studies to result in adecrease in mucositis. Subsequent randomized and controlled studies,however, have failed to demonstrate any benefit from treatment withthese agents (Loprinzi et al., 1995, Sem. Oncol. 22 Suppl. 3): 95-97;Epstein & Wong, 1994, Int. J. Radiation Oncology Biol. Phys. 28:693-698;Verdi et al., 1995, Oral Surg. Oral Med. Oral Pathol. Oral Radiol.Endod. 80:36-42).

Other therapies have been directed at decreasing oral flora and theextent of oral infections. Systemic treatment with G- and GM-CSF hasbeen shown to result in a decreased incidence of oral mucositis,presumably by allowing for more rapid neutrophil recovery and thus animproved ability to combat infection, although it has been postulatedthat the CSFs may have a more direct effect on the oral mucosa (Chi etal., 1995, J. Clin. Oncol. 13:2620-2628). Nonetheless, in one study,GM-CSF was reported to exacerbate mucositis (Cartee et al., 1994,Cytokine 7:741-477). Benzydamine hydrochloride, a nonsteroidal drug withanalgesic and antimicrobial properties, has been studied both inpatients undergoing radiation therapy and in patients receivingintra-arterial chemotherapy (Epstein et al., 1986, Oral Surg. Oral Med.Oral Pathol. 62:145-148; Epstein et al., 1989, Int. J. RadiationOncology Biol. Phys. 16:1571-1575) but without much success.

Chlorhexidine, an antimicrobial mouth rinse, has also been usedextensively in the treatment and prevention of oral mucositis (Ferrettiet al., 1990, Bone Marrow Transplan. 3:483-493; Weisdorf et al., 1989,Bone Marrow Transplan. 4:89-95). It has been noted, however, that theefficacy of chlorhexidine is significantly decreased in saliva, and thatthis compound is relatively ineffective against the Gram negativebacteria that tend to colonize the oral cavity in patients undergoingradiation therapy (Spijkervet et al., 1990, Oral Surg. Oral Med. OralPathol. 69:444-449). In addition, at least one study has shown that theuse of chlorhexidine may be detrimental and result in a higher incidenceof mucositis (Foote et al., 1994, J. Clin Oncol. 12:2630-2633).

Several studies have shown that the use of a vancomycin paste andantibiotic lozenges containing polymixin B, tobramycin and amphotericinB in patients undergoing myelosuppresive chemotherapy or radiationtherapy can result in a decrease in oral mucositis and in the incidenceof sepsis due to alpha hemolytic streptococci (Barker et al., 1995, J.Ped. Hem. Oncol. 17:151-155; Spijkervet et al., 1991, In: IrradiationMucositis, Munksgaard Press, pp. 43-50).

Other methods of treating or preventing mucositis using a variety offormulations have been reported. U.S. Pat. No. 5,545,668 to Skubitz etal. describes formulations containing glutamine. U.S. Pat. No. 5,635,489to Haley, U.S. Pat. No. 4,961,926 to Gabrilove, and U.S. Pat. No.5,102,870 to Florine et al., describe treatments using formulationscontaining growth factors or stimulating factors. Formulations containantimicrobial peptides such as protegrin as the effective ingredienthave also been described by U.S. Pat. No. 6,025,326 to Steinberg et. al.A triclosan formulation for treating mucositis was reported in U.S. Pat.No. 5,945,089 to Libin.

Despite the clear need for therapeutic agents to treat oral mucositis,none of the treatments provide significant long-term relief or decreasethe severity or duration of mucositis. As a result, there is no standardtreatment for oral mucositis.

Rothwell and Spektor (Special Care in Dentistry, January-February 1990,pages 21-25) have shown that patients to whom an oral rinse containingtetracycline, diphenhydramine, nystatin, and hydrocortisone wasadministered developed less severe mucositis than patients receiving acontrol rinse. The concentrations of the active ingredients in thisstudy were tetracycline, 500 mg; nystatin, 1,200,000 U; hydrocortisone,100 mg; and diphenhydramine elixir, 10 ml made up to a total volume of250 ml. The tetracycline was unstable in solution with the otheringredients and was therefore administered in a separate solution.

WO 99/45910 by Sonis and Fey describes a method for treating andpreventing mucositis by administering a non-steroidal anti-inflammatory(NSAID), an inflammatory cytokine inhibitor, or a mast cell inhibitorand second different therapeutic agent which is an NSAID, aninflammatory cytokine inhibitor, a mast cell inhibitor, a matrixmetalloproteinase (MMP) inhibitor or a nitric oxide inhibitor. There arefurther claims where the MMP inhibitor is a tetracycline. These complexmixtures appear to reduce mucositis in animal models but the relativeefficacies of the different active agents and effective dosages areunclear. Most of the active ingredients have side effects if absorbedsystemically at effective dosages. Only the compositions containing thetetracyclines appear to significantly reduce the symptoms of themucositis.

It is therefore an object of the present invention to provide a methodand composition to decrease the duration and/or severity of mucositis byadministering a composition containing a tetracycline as the activeingredient which is not absorbed systemically.

It is a further object of the present invention to provide a treatmentthat is safe, efficacious and easy for the patient to use.

SUMMARY OF THE INVENTION

Mucositis is treated and/or prevented by administrating to a patient aformulation comprising a tetracycline that is poorly absorbed from thegastro-intestinal tract. The tetracycline may be in the form of apharmaceutically acceptable salt or a base. The formulations mayoptionally also contain an antifungal agent to prevent fungal overgrowthdue to reduction in the normal oral flora by the tetracycline. Suchcompositions have the advantage of treating the entire gastro-intestinaltract since the active ingredient is not removed from the tract viaabsorption. Further, such compositions minimize systemic exposure andaccompanying side effects.

DETAILED DESCRIPTION OF THE INVENTION

I. Topical Tetracycline Formulations

Topical formulations for treating mucositis have been developed. Theseinclude as the active ingredient to treat the mucositis a tetracyclinetype compound that is poorly absorbed when administered orally ortopically to the mucosa, a carrier which may be a solvent or suspendingagent and include excipients modifying the viscosity, taste, stability,adherence or release properties, and optionally an anti-fungal agent.

A. Tetracyclines

As used herein, tetracyclines include compounds that may or may not haveantibiotic activity. The tetracyclines described herein are those whichare poorly absorbed when administered orally. Compounds which havebioavailibilities of about 10% or less are considered to be poorlyabsorbed. The tetracyclines are known to have pharmacological activitiessuch as matrix metalloproteinase, nitric oxide synthetase and caspaseinhibition that are independent of their antibiotic properties. Theseactivities may be important in the treatment and prevention ofmucositis. It is known that these pharmacological activities may beassociated with tetracyclines that do not have significant antibioticproperties.

Tetracyclines are defined by the following structure:

wherein R₁-R₅ may be a hydrogen atom, a halogen atom, a hydroxyl group,or any other organic composition comprising from 1-8 carbon atoms andoptionally include a heteroatom such as nitrogen, oxygen, in linear,branched, or cyclic structural formats.

A wide range and diversity of embodiments within the definition of theabove structure as are described within Essentials of MedicinalChemistry John Wiley and Sons, Inc., 1976, pages 512-517, the text ofwhich is incorporated by reference herein. Preferably R₁ and R₂ arehydrogen or a hydroxyl group; R₃ is hydrogen or a methyl group; R₄ is ahydrogen atom, a halogen, or a nitrogen containing entity; and R₅ is ahydrogen atom, or nitrogen containing ring structure. The commonly knowntetracycline analogues and derivatives include the following:oxytetracycline; chlortetracycline; demeclocycline; doxycycline;minocycline; rolitetracycline; lymecycline; sancycline; methacycline;apicycline; clomocycline; guamecycline; meglucycline; mepyclcline;penimepicycline; pipacycline; etocycline, penimocycline, andmeclocycline.

Tetracycline derivatives that can be used as described herein, includetetracycline derivatives modified at positions 1 through 4 and 10through 12, although these modifications may result in reduction inantibiotic properties, according to Mitscher, et al., J. Med. Chem.21(5), 485-489 (1978). The configuration of the 4 carbon is important tothe antibiotic properties of the tetracyclines. For the antibiotictetracyclines, carbon 4 is in the S configuration. The 4-epimers of thetetracyclines, which have the R configuration at the 4 carbon, havesignificantly reduced antibiotic activity. Other such non-antibiotictetracycline analogs include the 4-de(dimethylamino) derivatives of thetetracyclines listed in the above paragraph. Specific examples include:6-demethyl-6-deoxy-4-dedimethylaminotetracycline;6-demethyl-6-deoxy-4-dedimethylamino-7-dimethylaminotetracycline;6-demethyl-6-deoxy-4-dedimethylamino-7-chloro-tetracycline;4-hydroxy-4-dedimethylaminotetracycline;6a-deoxy-5-hydroxy-4-dedimethylaminotetracycline;4-dedimethylamino-5-oxytetracycline, and4-dedimethylamino-11-hydroxy-12a-deoxytetracycline. Further examples oftetracyclines with reduced antibiotic activity include6-α-benzylthiomethylenetetracycline, 6-fluoro-6-demethyltetracycline,and 11α-chlorotetracycline.

Other tetracycline related compounds that can be used as describedherein are the 9-((substituted)amido)tetracyclines. The latter includethe compounds described in U.S. Pat. Nos. 5,886,175, 5,284,963,5,328,902, 5,386,041, 5,401,729, 5,420,272, and 5,430,162.

Preferred poorly absorbed tetracyclines include compounds of thefollowing structure:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ can be H, C1-C3 alkyl,phenyl, and aryl groups; andwherein X is an H, alkyl, alkoxy, phenoxy, aryloxy, amino group, amide,acyl, and halo group; and pharmaceutically acceptable salts thereof.

The most preferred compound of this general structure is

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are H;

wherein R³ is CH₃; and

wherein X is a chloro group. The generic name for this compound ismeclocycline.

The preparation of meclocycline and its analogs and derivatives areknown. For example, U.S. Pat. No. 3,966,808 to Luciano discloses methodsfor manufacturing 6-methylenetetracyclines.

B. Pharmaceutically Acceptable Carriers

The formulations may be prepared as a liquid, semi-solid, or solidcontaining an amount of a poorly absorbed tetracycline that is effectiveto treat or prevent mucositis. Generally, these compositions containabout 0.001 to 1 mg/mL of the tetracycline.

The compositions are topically administered to the oral mucosa and thenswallowed. Formulation types suitable for this route of administrationinclude liquids applied as mouthrinses; solid dosage forms that maydissolve in the mouth; and semisolids that may be applied to oral cavitysurfaces.

Tetracyclines in general may not be sufficiently stable in aqueoussolutions to permit formulations with long shelf lives at roomtemperature, i.e. a year or more, to be prepared. Stability of thetetracyclines varies greatly with structure. However, solids forre-constitution as aqueous based solutions prepared either by thepatient or by a pharmacist prior to administration to the patient can beused, even for the least stable members of the class. Also polyvalentmetal ion complexes may be prepared that are stable in contact withwater at room temperature for two years or more. Examples are thecalcium and magnesium complexes. These complexes may be suspensions inwater.

The stability of the tetracyclines in aqueous solutions is pH dependent.Procedures for choosing the optimum pH and buffering agents are wellknown. Other factors that affect stability in solution are also wellknown. For example, antioxidants may be added to reduce the rate ofdegradation due to oxidation.

In addition to the tetracycline and antifungal agents, an aqueous liquidpreparation may contain buffers, surfactants, humectants, preservatives,flavorings, stabilizers (including antioxidants), colorants, and otheradditives used in preparations administered into the oral cavity.

The compositions used as mouthwashes preferably should have a pH of 3.5to 8. A pH of 4 to 6.5 is most preferable. A preparation having a pH ofless than about 4 would be likely to cause a stinging sensation.Furthermore, the preparations having a higher pH are often unpleasant touse. The active agents need not be in solution to be effective. Theactive agents may be present wholly or in part as suspensions in aqueoussolutions used as carriers to provide liquid compositions.

The preparations are buffered as necessary to provide the appropriatepH. Appropriate buffer systems include citrate, acetate, tromethamineand benzoate systems. However, any buffer system commonly used forpreparing medicinal compositions would be appropriate. While the vehicleused generally is primarily water, other vehicles may be present such asalcohols, glycols (polyethylene glycol or polypropylene glycol areexamples), glycerin, and the like may be used to solubilize the activeagents. Surfactants may include anionic, nonionic, amphoteric andcationic surfactants, which are known in the art as appropriateingredients for mouthwashes.

Liquid formulations may contain additional components to improve theeffectiveness of the product. For example, component(s) may be added toincrease viscosity to provide improved retention on the surfaces of theoral cavity. Suitable viscosity increasing agents include carboxyalkyl,hydroxyalkyl, and hydroxyalkyl alkyl celluloses, xanthan gum,carageenan, alginates, pectins, guar gum, polyvinylpyrolidone, andgellan gums. High viscosity formulations may cause nausea inchemotherapy and radiation patients and are therefore not preferred.Gellan gums are preferred as viscosity modifying agents since aqueoussolutions containing certain gellan gums may be prepared so that theywill experience an increase in viscosity upon contact with electrolytes.Saliva contains electrolytes that will interact with such a gellancontaining solution so as to increase their viscosity.

Flavorings used in the mouthrinse art such as peppermint, citrusflavorings, berry flavorings, vanilla, cinnamon, and sweeteners, eithernatural or artificial, may be used. Flavorings that are known toincrease salivary electrolyte concentrations may be added to increasethe magnitude of the viscosity change. The increased viscosity willpromote retention of the solutions in the oral cavity and providegreater effectiveness due to increased contact time with the affectedtissues.

In order to improve the patient acceptability, it is desirable to add anappropriate coloring and/or flavoring material. Any pharmaceuticallyacceptable coloring or flavoring material may be used.

Additional antimicrobial preservatives may be component of theformulation in cases where it is necessary to inhibit microbial growth.Suitable preservatives include, but are not limited to the alkylparabens, benzoic acid, and benzyl alcohol. The quantity of preservativemay be determined by conducting standard antimicrobial preservativeeffectiveness tests such as that described in the United StatesPharmacopoeia.

Suitable solid dosage forms include powders or tablets that are designedfor constitution as solutions by dissolution or suspension in a liquidvehicle and include troches, pastilles or lozenges that dissolve slowlyin the mouth. For convenience of use, solids designed to be dissolved toprepare a liquid dosage form prior to administration preferably arerapidly dissolving. Technologies to produce rapidly dissolving solidsare well known in the art. These include spray-drying, freeze-drying,particle size reduction and optimizing the pH of the dissolution medium.

The solubilities of tetracyclines are a complex function of pH sincethey have several ionizable functional groups. Tetracyclines generallyhave a minimum in their pH-solubility curves between a pH of 3 and 6.The rate of dissolution of acidic salts may be increased by dissolvingin a neutral to basic buffer. Dispersal of such salts may optimally bedone at low pH.

C. Other Active Agents

Other medicinal agents may be added for purposes of alleviating otherundesirable conditions in the mouth. Such agents may include, forexample, local anesthetics, antibacterial agents, and emollients, aswell as anti-fungal agents.

Anti-Fungal Agents

Antibiotic tetracyclines applied topically in the oral cavity may reducethe number of susceptible flora to such an extent that competitiveconditions that hold non-susceptible organisms in check may not beeffective. In particular, fungi, which are not susceptible totetracyclines, may increase drastically in number. To avoid this, anantifungal agent may be added to the composition. Examples of antifungalagents that have been shown to be effective in preventing or treatingfungal overgrowth are nystatin and clotrimazole. These agents may beadded to a liquid tetracycline dosage form as a powder to form asuspension. The approved dosage for Clotrimazole, 10 mg is three times aday for mucositis. The approved dosage of Nystatin is 200,000 to 400,000units, 4 to 5 times a day for up to 14 days in pastilles.

Examples of local anesthetics are lidocaine and a eutectic mixture oflidocaine and prilocaine. Lidocaine is administered in solution at aconcentration of 2%, at a dose of 15 ml, at intervals of not less thanthree hours. The eutectic mixture is equimolar, administered at a totalconcentration of up to 5%. Either could be incorporated in an aerosol atsimilar doses.

II. Methods of Treatment

Methods of using the formulations disclosed herein generally involveapplying the formulations topically to mucosal surfaces of the oralcavity and gastro-intestinal tract. One to six applications per daybeginning 24 hours before chemotherapy or radiation until conclusion oftreatment are made. The typical volume of a mouthwash would be between5-15 ml.

Therapy is continued for as long as the patient is receiving radiationor chemotherapy.

The present invention will be further understood by reference to thefollowing non-limiting examples.

Methods and Materials

The following animal model was used to demonstrate the effectiveness ofthe poorly absorbed tetracyclines in treating mucositis.

Hamsters were randomly assigned to treatment groups with eight (8)animals per group. Each group was treated either with a drug solution ora control, water.

Animals were dosed three times a day for 22 days. The first dose wasapplied on day—1. Either a solution of the drug or water alone wasapplied in a volume of 0.1 ml three times per day.

Mucositis was induced by acute radiation exposure of the check pouch. Asingle dose of radiation (35 Gy/dose) was administered to all animals onDay 0. Prior to irradiation, animals were anesthetized with anintraperiotoneal injection of sodium pentobarbital (80 mg/kg) and theleft buccal pouch was everted, fixed and isolated using a lead shield.

Beginning on day 6 and continuing every other day up to day 28, thecheek pouch was photographed. On days that photographs were taken, priorto the first dosing of the day, the animals were anesthetized using aninhalation anesthetic and the left cheek pouch of each animal was rinsedvigorously with sterile water to remove residual food debris or foreigncontamination and blotted dry with a gauze sponge. The appearance of thecheek pouch was scored visually by comparison to a validatedphotographic scale, ranging from 0 for normal to 5 for severe ulceration(clinical scoring). In descriptive terms, this scale is defined asfollows:

-   Score Description-   0 Pouch completely healthy. No erythema or vasodilatation-   1 Light to severe erythema and vasodilatation. No erosion of mucosa-   2 Severe erythema and vasodilatation. Erosion of superficial aspects    of mucosa leaving denuded areas. Decreased stippling of mucosa-   3 Formation of off-white ulcers in one or more places. Ulcers may    have a yellow/gray color due to pseudomembrane formation. Cumulative    size of ulcers up to ¼ of the pouch surface. Severe erythema and    vasodilatation-   4 Cumulative size of ulcers ¼ to ½ of the pouch surface. Loss of    pliability. Severe erythema and vasodilatation-   5 Virtually all of pouch is ulcerated. Loss of pliability (pouch can    only partially be extracted from mouth).

A score of 1-2 represents mild stage of the disease, whereas a score of3-5 indicates moderate to severe mucositis.

These examples demonstrate that the tetracycline compositionssignificantly reduce the severity of mucositis when administeredtopically to the oral mucosa. Further they show that meclocycline whichis poorly absorbed is as effective as a well absorbed tetracycline ortetracycline HO.

EXAMPLE 1 Treatment with Meclocycline Sulfosalicylate (0.1 mg/ml)

Eight hamsters were treated as described above with 0.1 mL of aqueoussolutions containing 0.1 mg/mL meclocycline sulfosalicylate. Thesolution was prepared by dissolving meclocycline in an aqueous solutionof a tromethamine buffer. Significantly lower scores were found in thegroup treated with the meclocycline solution than a group of hamsterstreated with a placebo control consisting of the solution withoutmeclocycline. Relative to the control group, the group treated withmeclocycline had a reduction of more than 75% in the number of animaldays with scores of 3 or more.

EXAMPLE 2 Treatment with Tetracycline Hydrochloride (0.1 mg/ml)

Eight hamsters were treated as described above with 0.1 mL of aqueoussolution containing 0.1 mg/ml tetracycline hydrochloride. Significantlylower scores were found in the group treated with the tetracyclinesolution than a group of hamsters treated with a placebo controlconsisting of the solution without tetracycline. Relative to the controlgroup, the group treated with tetracycline had a reduction of more than75% in the number of animal days with scores of 3 or more.

These examples demonstrate that the tetracycline compositionssignificantly reduce the severity of mucositis when administeredtopically to the oral mucosa. Further they show that meclocycline whichis poorly absorbed is as effective as a well absorbed tetracycline.

EXAMPLE 3 Freeze-Dried Meclocycline Gellan Gum Formulations

Meclocycline hydrochloride powder formed by freeze drying in bulk isadded to a solution containing gellan gum at a concentration of 0.5mg/mL. The tetracycline concentration is 0.1 mg/mL. The solution alsocontains methyl and propyl parabens as antimicrobial preservatives atconcentrations of 0.18% and 0.02%, respectively and tromethamine buffer.

EXAMPLE 4 Miconized Meclocycline Gellan Gum Buffered Formulations

Meclocycline-hydrochloride powder formed by micronization is added to asolution containing gellan gum at a concentration of 0.5 mg/mL. Thetetracycline concentration is 0.05 mg/mL. The solution also containsmethyl and propyl parabens as antimicrobial preservatives atconcentrations of 0.18% and 0.02%, respectively and tromethamine buffer.

EXAMPLE 5 Spray-Dried Meclocycline Gellan Gum Formulation

Meclocycline hydrochloride powder formed by spray drying is added to asolution containing gellan gum at a concentration of 0.5 mg/mL. Thetetracycline concentration is 0.01 mg/mL. The solution also containsmethyl and propyl parabens as antimicrobial preservatives atconcentrations of 0.18% and 0.02%, respectively and tromethamine buffer.

EXAMPLE 6 Micronized Meclocycline Buffered Formulation

Meclocycline sulfosalicylate powder formed by micronization is added towater. The suspension is added to a second solution containing atromethamine buffer to form a mixture with a pH of approximately 8.

EXAMPLE 7 Meclocyline Coated Pellets

Pellets comprised of an inner core of tromethamine buffer and a coatingof meclocycline hydrochloride embedded in methyl cellulose is added towater to form a mouth rinse. The concentration of the tetracycline inthe solution is 0.1 mg/mL.

EXAMPLE 8 Meclocycline Tablets

A rapidly disintegrating tablet containing meclocycline sulfosalicylateis added to water. The tablet disintegrates and a second tabletcontaining a buffer is added to the solution to raise the pH so that thetetracycline rapidly dissolves.

EXAMPLE 9 Meclocycline Calcium Complex Suspension

A meclocyline calcium complex suspension is formed by addition of thehydrochloride salt of meclocycline to a solution of calcium lactate,which has been made basic, by the addition of sodium hydroxide. Thesolution also contained methyl and propyl parabens as antimicrobialpreservative and EDTA and sodium bisulfite as antioxidants. Thesolutions were sparged with nitrogen to remove dissolved oxygen prior toaddition of the sodium bisulfite. The mixture is deaerated.

EXAMPLE 10 Meclocycline Suspension

A suspension of meclocycline sulfosalicylate is formed by addition ofmicronized drug to an aqueous solution containing 0.5% gellan gum andmethyl and propyl parabens as antimicrobial preservative.

EXAMPLE 11 Meclocycline Sulfosalicylate Suspension

A suspension of meclocycline sulfosalicylate is formed by addition ofmicronized drug to a unit dose quantity of an aqueous solutioncontaining 0.5% gellan gum. No antimicrobial preservative is requiredsince the formulation is used immediately after preparation.

EXAMPLE 12 Aeorosolized Micronized Meclocycline

A metered dose aerosol container is filled with micronized meclocyclinesulfosalicylate and a non-FREON™ propellant. The container is equippedwith a valve for delivering 500 mcg per actuation. The container is alsoequipped with a tube for directing the aerosol to the interior of themouth.

EXAMPLE 13 Meclocycline Oral Rinse Solution

A powder containing meclocycline hydrochloride and buffer to promoterapid dissolution is prepared by granulation. The powder is dissolved inwater to form an oral rinse solution containing 0.05 mg/mL meclocycline.

EXAMPLE 14 Effervescent Tablet Containing Meclocycline Formulation

An effervescent tablet containing meclocycline sulfosalicylate andsodium bicarbonate. The tablet is dissolved in water to form an oralrinse solution containing 0.1 mg/mL meclocycline.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the present application described herein. Suchequivalents are intended to be encompassed by the following claims.

1. A pharmaceutical composition for treating or preventing mucositiscomprising as the sole active agents an effective amount of a poorlyabsorbed tetracycline defined by the following structure:

wherein R₁-R₅ may be a hydrogen atom, a halogen atom, a hydroxyl group,or any other organic composition comprising from 1-8 carbon atoms andoptionally include a heteroatom such as nitrogen, oxygen, in linear,branched, or cyclic structural formats, alone or in combination with acompound selected from the group consisting of local anesthetics andantifungal agents, in a carrier for topical administration to themucosa.
 2. The composition of claim 1 wherein the carrier for topicaladministration to the mucosa of the oral cavity and gastrointestinaltract is a mouthwash formulation.
 3. The composition of claim 1 whereinR₁ and R₂ are hydrogen or a hydroxyl group; R₃ is hydrogen or a methylgroup; R₄ is a hydrogen atom, a halogen, or a nitrogen containingentity; and R₅ is a hydrogen atom, or nitrogen containing ringstructure.
 4. The composition of claim 1 wherein the tetracycline ismodified by substitution of H at carbon 9 by a substituted amido group.5. The composition of claim 1 wherein the tetracycline is modified atany of positions 1 through 4 and 10 through
 12. 6. The composition ofclaim 1 having the following structure:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ can be H, C1-C3 alkyl,phenyl, and aryl groups; and wherein X is an H, alkyl, alkoxy, phenoxy,aryloxy, amino group, amide, acyl, and halo group; and pharmaceuticallyacceptable salts thereof.
 7. The composition of claim 6 wherein R¹, R²,R⁴, R⁵, R⁶, R⁷, and R⁸ are H; wherein R³ is CH₃; and wherein X is achloro group.
 8. The composition of claim 1 wherein the carrier fortopical administration to the mucosa of the oral cavity andgastro-intestinal tract is selected from the group consisting of alozenge, tablet, paste and gel.
 9. The composition of claim 1 whereinthe carrier for topical administration comprises the tetracycline coatedonto or encapsulated into a carrier selected from the group consistingof powders, pellets, microcapsules, liposomes, and emulsions.
 10. Thecomposition of claim 9 wherein the tetracycline is formulated as a drypowder.
 11. The composition of claim 1 wherein less than 10% of thetetracycline is absorbed into the systemic circulation when topicallyadministered to the mouth and then swallowed.
 12. The composition ofclaim 1 wherein the tetracycline is in the form of a polyvalent metalion complex.
 13. The composition of claim 12 wherein the polyvalentmetal ion is calcium or magnesium.
 14. The composition of claim 1wherein the tetracycline is formulated to be topically administered tothe mucosa as an aerosol.